IP₃R at ER-Mitochondrial Contact Sites: Beyond the IP₃R-GRP75-VDAC1 Ca²⁺ Funnel

Membrane contact sites (MCS) circumvent the topological constraints of functional coupling between different membrane-bound organelles by providing a means of communication and exchange of materials. One of the most characterised contact sites in the cell is that between the endoplasmic reticulum and the mitochondrial (ERMCS) whose function is to couple cellular Ca²⁺ homeostasis and mitochondrial function. Inositol 1,4,5-trisphosphate receptors (IP₃Rs) on the ER, glucose-regulated protein 75 (GRP 75) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane are the canonical component of the Ca²⁺ transfer unit at ERMCS. These are often reported to form a Ca²⁺ funnel that fuels the mitochondrial low-affinity Ca²⁺ uptake system. We assess the available evidence on the IP₃R subtype selectivity at the ERMCS and consider if IP₃Rs have other roles at the ERMCS beyond providing Ca²⁺. Growing evidence suggests that all three IP₃R subtypes can localise and regulate Ca²⁺ signalling at ERMCS. Furthermore, IP₃Rs may be structurally important for assembly of the ERMCS in addition to their role in providing Ca²⁺ at these sites. Evidence that various binding partners regulate the assembly and Ca²⁺ transfer at ERMCS populated by IP₃R-GRP75-VDAC1, suggesting that cells have evolved mechanisms that stabilise these junctions forming a Ca²⁺ microdomain that is required to fuel mitochondrial Ca²⁺ uptake.